Immunogenetics of xenotransplantation

Oliveira, Marco Carvalho; Valdivia, Emilio; Blasczyk, Rainer; Figueiredo, Constança

doi:10.1111/iji.12526

Cited by 12 publications

(4 citation statements)

References 172 publications

(248 reference statements)

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“…The prominent pathobiological barriers to successful clinical use of xenotransplantation include the rapid activation of innate cellular responses against the graft, and at later stage, further rejection of the organ by the adaptive immune system ( 9 , 10 ). As important, coagulation dysregulation and inflammation intervene in the rejection process.…”

Section: Introductionmentioning

confidence: 99%

Current status of xenotransplantation research and the strategies for preventing xenograft rejection

Zhou

Wang

et al. 2022

Front. Immunol.

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Transplantation is often the last resort for end-stage organ failures, e.g., kidney, liver, heart, lung, and pancreas. The shortage of donor organs is the main limiting factor for successful transplantation in humans. Except living donations, other alternatives are needed, e.g., xenotransplantation of pig organs. However, immune rejection remains the major challenge to overcome in xenotransplantation. There are three different xenogeneic types of rejections, based on the responses and mechanisms involved. It includes hyperacute rejection (HAR), delayed xenograft rejection (DXR) and chronic rejection. DXR, sometimes involves acute humoral xenograft rejection (AHR) and cellular xenograft rejection (CXR), which cannot be strictly distinguished from each other in pathological process. In this review, we comprehensively discussed the mechanism of these immunological rejections and summarized the strategies for preventing them, such as generation of gene knock out donors by different genome editing tools and the use of immunosuppressive regimens. We also addressed organ-specific barriers and challenges needed to pave the way for clinical xenotransplantation. Taken together, this information will benefit the current immunological research in the field of xenotransplantation.

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Section: Introductionmentioning

confidence: 99%

Current status of xenotransplantation research and the strategies for preventing xenograft rejection

Zhou

Wang

et al. 2022

Front. Immunol.

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“…Once there is a better understanding of the molecular mechanisms behind the immunological activation occurring after implantation of decellularized human heart valves, the opportunity may arise to silence the respective antigens before implantation ( 11 ). As the field of xenotransplantation is rapidly evolving, new initiatives using decellularized xenogeneic heart valves will likely play a role in the future ( 15 ), possibly in combination with autologous stem cell recellularization using induced pluripotent stem cells (iPS) ( 16 , 17 ). Our group already has started to use decellularized heart valves from genetically modified pigs in primate models for pulmonary valve replacement.…”

Section: Discussionmentioning

confidence: 99%

Serial assessment of early antibody binding to decellularized valved allografts

Oripov

Ramm

Falk

et al. 2022

Front. Cardiovasc. Med.

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ObjectivesDecellularized homograft valves (DHV) appear to elicit an immune response despite efficient donor cell removal.Materials and methodsA semiquantitative Dot-Blot analysis for preformed and new recipient antibodies was carried out in 20 patients following DHV implantation on days 0, 1, 7, and 28 using secondary antihuman antibodies. Immune reactions were tested against the implanted DHV as well as against the stored samples of 5 non-implanted decellularized aortic (DAH) and 6 pulmonary homografts (DPH).ResultsIn this study, 20 patients (3 female and 17 male patients) were prospectively included, with a median age of 18 years and an IQR of 12–30 years. Six patients received DPH and 14 received DAH. The amount of antibody binding, averaged for all patients, decreased on post-operative days 1 and 7 compared to pre-operative values; and on day 28, antibody binding reached close to pre-operative levels (16.8 ± 2.5 on day 0, 3.7 ± 1.9 on day 1, 2.3 ± 2.7 on day 7, and 13.2 ± 3.7 on day 28). In comparison with the results in healthy controls, there was a higher amount of antibody binding to DAH than to DPH. The mean number of arbitrary units was 18.4 ± 3.1 in aortic and 12.9 ± 4.5 in pulmonary DHV (p = 0.140). Male patients exhibited higher antibody binding to aortic DHV than female patients (19.5 ± 2.1 vs. 1.6 ± 6.7). The p-value calculation was limited, as only two female patients received DAH. There was no correlation between the amount of overall antibody binding to DHV with respect to donor age (Kruskal–Wallis test p = 0.550). DHV recipients with a sex mismatch to the donor showed significantly less antibody binding (6.5 ± 1.8 vs. 13.7 ± 1.8; p = 0.003). Our main finding was an increase in antibody binding in younger patients receiving decellularized aortic allografts. This increase was higher in patients with early degeneration signs but was not specific to the individual DHV implanted nor previous DHV implantation. Antibody binding toward explanted DHV was significantly increased in implicating antibody-mediated DHV degeneration.ConclusionSerial assessment of tissue-specific antibody binding revealed an increase in some patients within 4 weeks after surgery, who subsequently developed early signs of allograft degeneration. Further studies with larger sample sizes are needed to confirm the prognostic relevance of increased antibody activity in addition to targeted research efforts to identify the molecular agents triggering this type of antibody response.

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“…Immune cell infiltration of tissue and solid organ xenografts starts with neutrophils as an early responding cell population, followed by macrophages and T cells 48 . The innate immune system, which is composed mainly of phagocytic cells (monocytes, macrophages and neutrophils), natural killer (NK) cells, as well as inflammatory mediator releasing granulocytes (basophils, eosinophils and mast cells), recognizes non-selfness of xenogeneic cells, like pathogen-associated molecular patterns (PAMPs), leading to the activation of innate immune cells 49 . Neutrophils are directly activated by xenogeneic cells and indirectly through xenoreactive natural antibodies (XNA) and complement to boost immune responses to eradicate xenogeneic cells 50 .…”

Section: Immune-mediated Barriers For Successful Clinical Xenogeneic Cell Therapymentioning

confidence: 99%

Utilizing Xenogeneic Cells As a Therapeutic Agent for Treating Diseases

Huang

Yang²,

Shyr

2021

Cell Transplant

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The utilization of biologically produced cells to treat diseases is a revolutionary invention in modern medicine after chemically synthesized small molecule drugs and biochemically made protein drugs. Cells are basic units of life with diverse functions in mature and developing organs, which biological properties could be utilized as a promising therapeutic approach for currently intractable and incurable diseases. Xenogeneic cell therapy utilizing animal cells other than human for medicinal purpose has been studied as a new way of treating diseases. Xenogeneic cell therapy is considered as a potential regenerative approach to fulfill current unmet medical needs because xenogeneic cells could be isolated from different animal organs and expanded ex vivo as well as maintain the characteristics of original organs, providing a versatile and plenty cell source for cell-based therapeutics beside autologous and allogeneic sources. The swine species is considered the most suitable source because of the similarity with humans in size and physiology of many organs in addition to the economic and ethical reasons plus the possibility of genetic modification. This review discusses the old proposed uses of xenogeneic cells such as xenogeneic pancreatic islet cells, hepatocytes and neuronal cells as a living drug for the treatment of degenerative and organ failure diseases. Novel applications of xenogeneic mesenchymal stroma cells and urothelial cells are also discussed. There are formidable immunological barriers toward successful cellular xenotransplantation in clinic despite major progress in the development of novel immunosuppression regimens and genetically multimodified donor pigs. However, immunological barriers could be turn into immune boosters by using xenogeneic cells of specific tissue types as a novel immunotherapeutic agent to elicit bystander antitumor immunity due to rejection immune responses. Xenogeneic cells have the potential to become a safe and efficacious option for intractable diseases and hard-to-treat cancers, adding a new class of cellular medicine in our drug armamentarium.

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Immunogenetics of xenotransplantation

Cited by 12 publications

References 172 publications

Current status of xenotransplantation research and the strategies for preventing xenograft rejection

Current status of xenotransplantation research and the strategies for preventing xenograft rejection

Serial assessment of early antibody binding to decellularized valved allografts

Utilizing Xenogeneic Cells As a Therapeutic Agent for Treating Diseases

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